Synuclein deposition and non-motor symptoms in Parkinson disease

Abstract

Parkinson disease (PD) is a multisystem neurodegenerative disorder clinically characterized by motor and non-motor (NM) symptoms. The causes of NM symptoms in PD, many of which antedating motor dysfunction, are multifocal and unlikely explained by single lesions. They include olfactory, autonomic, sensory, skin, sleep, visual, neuropsychiatric, and other manifestations. Most NM features in PD are related to α-synuclein pathology which, in addition to the dopaminergic striatonigral system, involves non-nigral brainstem nuclei, sympathetic, parasympathetic, enteric and pelvic plexuses, cardiac systems, submandibular gland, adrenal medulla, skin, retina, and other visceral organs. This suggests a topographical and chronological spread of lesions, particularly in the prodromal stages of the disease, which, however, awaits further confirmation. A few animal models are available that recapitulate NM symptoms in human PD, but their validity is under discussion. More studies are warranted to refine the exact correlations between presymptomatic and late-developing NM features of PD and α-synuclein pathology as a basis for more effective preventive and therapeutic options of this devastating disease.

Introduction

Parkinson disease (PD), one of the most frequent neurodegenerative disorders, is no longer thought of as a complex motor disorder featuring bradykinesia, tremor, rigidity and postural instability related to degeneration of the dopaminergic striatonigral system, but a progressive multisystem disease with variegated motor and non-motor (NM) deficiencies, including impaired olfaction, gastrointestinal, genitourinary, cardiovascular and respiratory dysfunctions, sleep, sensory, visual, and neuropsychiatric disorders. Many of them antedate motor dysfunctions [1], and recent studies suggested a non-motor preclinical phase spanning up to 20 years and more [2]. Other NM deficits (e.g., insomnia, bladder disturbances, dementia) typically appear later in the course of PD and worsen with disease [3]. The clinical spectrum of NM symptoms in PD has been reviewed [1], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], as well as those in atypical and secondary parkinsonism [14]. The causes of NM symptoms in PD are multifactorial and linked to widespread distribution of α-synuclein (αSyn), the basic pathological protein aggregated in neurons, neurites, presynaptic terminals and glia as a hallmark in PD and other synucleinopathies [15], [16]. αSyn aggregation usually predates the formation of Lewy bodies (LB) and dystrophic neurites [17], [18], but does no necessarily correlate with LB pathology [19], [20], [21], [22]. It is not restricted to specific dopaminergic brainstem nuclei, but involves multiple areas of the central, autonomic, and peripheral nervous system, the retina, sympathetic and parasympathetic ganglia and nerves, skin, salivary glands, and other organs (for rev. see [23], [24]). The pathology of NM symptoms in PD has been reviewed recently [20], [25], [26], [27], [28]. The present review will briefly update the relations between αSyn deposition and the most frequent NM symptoms in PD, and discuss recent animal models and their probable relevance for this particular problem.